aminoglycosides

aminoglycosides
Name	Aminoglycosides
Use	Antibacterial
Biological target	Bacterial ribosome
ATC prefix	J01G

aminoglycosides are a class of potent bactericidal antibiotics derived from various species of actinomycetes, such as Streptomyces and Micromonospora. They are primarily used to treat serious infections caused by aerobic Gram-negative bacteria, including Pseudomonas aeruginosa and members of the Enterobacterales order. Their clinical utility is often limited by significant ototoxicity and nephrotoxicity, necessitating careful therapeutic drug monitoring. The discovery of streptomycin by Selman Waksman and his team at Rutgers University marked a pivotal advancement in the treatment of tuberculosis.

Mechanism of action

These agents exert their bactericidal effect by irreversibly binding to the 30S ribosomal subunit of the bacterial ribosome, a process that disrupts protein synthesis. This binding induces misreading of the mRNA template during translation, leading to the incorporation of incorrect amino acids and the production of nonfunctional or toxic polypeptides. Furthermore, they interfere with the initial steps of translation by blocking the formation of the initiation complex, which ultimately results in bacterial cell death. The action is concentration-dependent and requires an aerobic environment for uptake into bacterial cells, making them ineffective against anaerobic bacteria.

Clinical use

Due to their potency and potential toxicity, use is typically reserved for severe, often hospital-acquired, systemic infections. They are a cornerstone in the management of sepsis, particularly when caused by multidrug-resistant Gram-negative bacteria like Pseudomonas aeruginosa and Acinetobacter baumannii. They are also employed in combination with a beta-lactam antibiotic, such as penicillin or cephalosporin, for synergistic effect in treating infective endocarditis caused by Enterococcus faecalis or Viridans streptococci. Other specific uses include the treatment of plague caused by Yersinia pestis and as part of combination therapy for brucellosis and tularemia.

Adverse effects

The two most significant and dose-limiting toxicities are ototoxicity and nephrotoxicity. Ototoxicity can manifest as irreversible damage to the vestibular system or the cochlea, leading to symptoms like vertigo, ataxia, and sensorineural hearing loss; this risk is heightened with concurrent use of other ototoxic drugs like loop diuretics. Nephrotoxicity, often reversible, involves damage to the proximal tubule of the nephron, resulting in acute kidney injury characterized by elevated serum creatinine and blood urea nitrogen. Less common adverse effects include neuromuscular blockade, which can potentiate the effects of anesthetic agents and muscle relaxants, and rare allergic reactions.

Resistance

Bacterial resistance arises through several well-characterized mechanisms. The most common is enzymatic modification and inactivation by bacterial enzymes such as phosphotransferases, nucleotidyltransferases, and acetyltransferases, which are often encoded on plasmids or transposons. Another key mechanism involves reduced drug uptake due to mutations in the bacterial outer membrane or alterations in the electron transport chain required for active transport. A third mechanism is target-site modification through ribosomal RNA methyltransferase enzymes, which alter the 16S rRNA binding site and prevent drug attachment, a mechanism notably found in pathogens like Pseudomonas aeruginosa and members of the Enterobacterales.

Pharmacokinetics

They are highly hydrophilic compounds with poor oral bioavailability, necessitating administration via intravenous injection or intramuscular injection for systemic effect. They distribute widely in extracellular fluid but achieve poor penetration into the cerebrospinal fluid, bile, and prostate. A critical pharmacokinetic property is their concentration-dependent killing and significant post-antibiotic effect. They are eliminated almost exclusively by glomerular filtration in the kidney and are not metabolized, making their clearance directly proportional to creatinine clearance. This necessitates dosage adjustment in patients with renal impairment and often the use of therapeutic drug monitoring to guide therapy.

Classes and examples

The class is traditionally divided into two main groups based on the producing organism. Those derived from Streptomyces include the prototypical streptomycin, as well as kanamycin, tobramycin, and neomycin. Those derived from Micromonospora include gentamicin and netilmicin. A semi-synthetic derivative, amikacin, was developed from kanamycin to resist many common inactivating enzymes. Another important example is paromomycin, used primarily for the treatment of intestinal amoebiasis and leishmaniasis. The structural differences among these agents influence their spectrum of activity, potency, and susceptibility to various bacterial resistance mechanisms.

Category:Antibiotics